ES2639757T3 - Síntesis de 2-(1H-indazol-6-il)espiro[ciclopropan-1,3'-indolin]-2'-onas quirales - Google Patents

Síntesis de 2-(1H-indazol-6-il)espiro[ciclopropan-1,3'-indolin]-2'-onas quirales Download PDF

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ES2639757T3
ES2639757T3 ES11764989T ES11764989T ES2639757T3 ES 2639757 T3 ES2639757 T3 ES 2639757T3 ES 11764989 T ES11764989 T ES 11764989T ES 11764989 T ES11764989 T ES 11764989T ES 2639757 T3 ES2639757 T3 ES 2639757T3
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Graham Cumming
Narenda Kumar B. Patel
Bryan T. Forrest
Yong Liu
Sze-Wan Li
Peter Brent Sampson
Louise G. Edwards
Heinz W. Pauls
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University of Health Network
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A—HUMAN NECESSITIES
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    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract

Un procedimiento para preparar un compuesto de espiroindolinona representado por la siguiente Fórmula Estructural: **Fórmula** o una sal del mismo, que comprende la etapa de hacer reaccionar un compuesto de indolinona representado por la siguiente Fórmula Estructural: **Fórmula** con una base y un compuesto de indazol representado por la siguiente Fórmula Estructural: **Fórmula** en la que: cada uno de Ra y Rb es independientemente -H, halógeno, -C(O)OR1, -C(O)R1, -C(S)R1, -OC(O)R1-, -C(O)NR1R2, -C(S)NR1R2, -OC(O)NR1R2, -S(O)R1, -S(O)2R1, -SO3R1, -SO2NR1R2, -OR1, -SR1, -NR1R2, -NR2C(O)R1, -NR2S(O)R1, -NR2C(O)OR1, -NR2C(O)ONR1R2, -N(R2)C(O)NR1R2, -NR2SO2NR1R2, -NR2SO2R1; -NO2, -CN, -NCS; o dos grupos Ra en orto tomados conjuntamente forman -O-[CH2]p-O-, -S-[CH2]p-S- o -[CH2]q-; o un grupo alifático C1-10 opcionalmente sustituido con uno o más sustituyentes seleccionados del grupo consistente en halógeno, nitro, ciano, -N(R21)2, -C(O)N(R21)2, -C(O)N(R21)2, -NR21C(O)R21, -SO2R22, -SO2N(R21)2, -NR21SO2R22, -NR21C(O)OR21, -OC(O)N(R21)2, -NR21C(O)N(R21)2, -NR21C(O)ON(R21)2, -NR21SO2N(R21)2, -OR21, -SR21, halogenoalcoxi C1-10, -C(O)R21, -C(O)OR21 y -OC(O)R21; o (alquilen C0-10)-Ar1, en la que Ar1 es un grupo arilo C6-14 o un grupo heteroarilo de 5-14 miembros, cada uno opcional e independientemente sustituido con uno o más sustituyentes seleccionados del grupo consistente en halógeno, nitro, ciano, alquilo C1-10, halogenoalquilo C1-10, (halogenoalcoxi C1-10)alquilo C1-10, (alcoxi C1-10)alquilo C1-10, hidroxialquilo C1-10, aminoalquilo C1-10, (alquil C1-10-amino)alquilo C1-10, (dialquil C1-10 -amino)alquilo C1-10, -N(R21)2, -C(O)N(R21)2, -C(O)N(R21)2, -NR21C(O)R21, -SO2R22, -SO2N(R21)2, -NR21SO2R22, -NR21C(O)N(R21)2, -NR21C(O)ON(R21)2, -NR21SO2N(R21)2, -OR21, -SR21, halogenoalcoxi C1-10, -C(O)R21, -C(O)OR21, -OC(O)R21, fenilo y heteroarilo de 5-6 miembros, en los que dicho fenilo y dicho heteroarilo de 5-6 miembros están cada uno independiente y opcionalmente sustituido con uno o más sustituyentes seleccionados del grupo consistente en halógeno, hidroxi, nitro, ciano, amino, alquilo C1-3, halogenoalquilo C1-3, alcoxi C1-3 y halogenoalcoxi C1-3; cada R1 es independientemente: i) hidrógeno; ii) un grupo arilo C6-14 o un grupo heteroarilo de 5-14 miembros, cada uno opcional e independientemente sustituido con uno o más sustituyentes seleccionados del grupo consistente en halógeno, -NO2, -CN, -NCS, alifático C1-C10, (alquilen C1-10)-Ar10, -C(O)OR10, -C(O)R10, -C(S)R10, -OC(O)R10, -C(O)N(R11)2, -C(S)N(R11)2, -OC(O)N(R11)2, -S(O)R12, -S(O)2R12, -SO3R12, -SO2N(R11)2, -OR10, -SR10, -N(R11)2, -NR11C(O)R10, -NR11S(O)R12, -NR11C(O)OR12, -N(R11)C(O)N(R11)2, -NR11SO2N(R11)2 y -NR11SO2R12; o iii) un grupo alifático C1-10 opcionalmente sustituido con uno o más sustituyentes seleccionados del grupo consistente en halógeno, -NO2, -CN, -NCS, Ar10, -C(O)OR10, -C(O)R10, -C(S)R10, -OC(O)R10, -15 C(O)N(R11)2, -C(S)N(R11)2, -OC(O)N(R11)2, -S(O)R12, -S(O)2R12, -SO3R12, -SO2N(R11)2, -OR10, -SR10, -N(R11)2, -NR11C(O)R10, -NR11S(O)R12, -NR11C(O)OR12, -N(R11)C(O)N(R11)2, -NR11SO2N(R11)2 y -NR11SO2R12, a condición de que R1 sea distinto de hidrógeno cuando Ra o Rb sea -S(O)R1, -S(O)2R1, -SO3R1, -NR2S(O)R1 o -NR2SO2R1; y cada R2 es independientemente -H o alquilo C1-C6, o, tomado conjuntamente con NR1, forma un grupo heterocíclico no aromático opcionalmente sustituido con uno o más sustituyentes seleccionados del grupo consistente en >=O, >=S, halógeno, nitro, ciano, hidroxi, alquilo C1-6, halogenoalquilo C1-6, hidroxialquilo C1-6, 25 amino, alquil C1-6-amino, dialquil C1-6-amino, aminoalquilo C1-6, (alquil C1-6-amino)alquilo C1-6, (dialquil C1-6-amino)alquilo C1-6, (fenil)alquilo C1-6, (heteroaril de 5-6 miembros)alquilo C1-6, alcoxi C1-6, halogenoalcoxi C1-6, alquil C1-6-carboniloxi, alcoxi C1-6-carbonilo, alquil C1-6-carbonilo, fenilo y heteroarilo de 5-6 miembros; R3 es -H, halógeno, alquilo C1-6 o halogenoalquilo C1-6; R4 es -H, alquilo C1-6, fenilo, -C(O)(alquilo C1-6), -C(O)(fenilo), -C(O)O(alquilo C1-6), -C(O)O(fenilo), -S(O)2(alquilo C1-6) o -S(O)2(fenilo), en los que cada alquilo en los grupos representados por R4 está opcionalmente sustituido con uno o más sustituyentes seleccionados del grupo consistente en halógeno, hidroxi, nitro, ciano, amino, -C(O)NH2, fenilo, heteroarilo de 5-6 miembros, alcoxi C1-6, alquil C1-6-amino, 35 dialquil C1-6-amino y halogenoalcoxi C1-6, y en los que cada fenilo en los grupos representados por R4 está opcionalmente sustituido con uno o más sustituyentes seleccionados del grupo consistente en halógeno, hidroxi, nitro, ciano, amino, alquilo C1-6, halogenoalquilo C1-6, alcoxi C1-6 y halogenoalcoxi C1-6; R6 es hidrógeno, halógeno, nitro, ciano, R', -OR, -SR, -N(R)2, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -OC(O)N(R)2, -NRC(O)R, -NRC(O)OR, -SOR', -SO2R', -SO3R', -SO2N(R)2, -NRS(O)R', -NRSO2R', -NRC(O)N(R)2, -NRC(O)ON(R)2, o -NRSO2N(R)2; cada R10 es independientemente: i) hidrógeno; ii) un grupo arilo C6-14 o un grupo heteroarilo de 5-14 miembros, cada uno opcional e independientemente sustituido con uno o más sustituyentes seleccionados del grupo consistente en halógeno, nitro, ciano, hidroxi, alquilo C1-10, halogenoalquilo C1-10, (halogenoalcoxi C1-10)alquilo C1-10, 50 (alcoxi C1-10)alquilo C1-10, hidroxialquilo C1-10, aminoalquilo C1-10, (alquil C1-10-amino)alquilo C1-10, (dialquil C1-10-amino)alquilo C1-10, (fenil)alquilo C1-10, (heteroaril de 5-6 miembros)alquilo C1-10, amino, alquil C1-10-amino, dialquil C1-10-amino, alcoxi C1-10, halogenoalcoxi C1-10, alquil C1-10-carboniloxi, alcoxi C1-10-carbonilo y alquil C1-10-carbonilo; o iii) un grupo alquilo C1-10 opcionalmente sustituido con uno o más sustituyentes seleccionados del grupo consistente en halógeno, nitro, ciano, hidroxi, halogenoalquilo C1-10, alcoxi C1-10, halogenoalcoxi C1-10, amino, alquil C1-10-amino, dialquil C1-10-amino, alquil C1-10-carboniloxi, alcoxi C1-10-carbonilo, alquil C1-10-carbonilo y fenilo, estando dicho fenilo opcionalmente sustituido con uno o más sustituyentes seleccionados del grupo consistente en halógeno, hidroxi, nitro, ciano, amino, alquilo C1-60 3, halogenoalquilo C1-3, alcoxi C1-3 y halogenoalcoxi C1-3;
ES11764989T 2010-04-06 2011-04-06 Síntesis de 2-(1H-indazol-6-il)espiro[ciclopropan-1,3'-indolin]-2'-onas quirales Active ES2639757T3 (es)

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Application Number Priority Date Filing Date Title
US32133210P 2010-04-06 2010-04-06
US32132910P 2010-04-06 2010-04-06
PCT/CA2010/000518 WO2010115279A1 (en) 2009-04-06 2010-04-06 Kinase inhibitors and method of treating cancer with same
PCT/CA2011/000387 WO2011123947A1 (en) 2010-04-06 2011-04-06 Synthesis of chiral 2-(1h-indazol-6-yl)-spiro[cyclopropane-1,3'- indolin]-2'-ones

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